The biological default state of cell proliferation with
variation and motility, a fundamental principle for a
theory of organisms
Ana M. Soto, Giuseppe Longo, Maël Montévil, Carlos Sonnenschein
To cite this version:
Ana M. Soto, Giuseppe Longo, Maël Montévil, Carlos Sonnenschein. The biological default
state of cell proliferation with variation and motility, a fundamental principle for a theory of
organisms. Progress in Biophysics and Molecular Biology, Elsevier, 2016, From the Century of
the Genome to the Century of the Organism: New Theoretical Approaches, 122 (1), pp.16 23. .
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The biological default state of cell proliferation with variation and motility, a
fundamental principle for a theory of organisms
Ana M. Sotoa,b,∗, Giuseppe Longoa,b , Maël Montévilc,d , Carlos Sonnenscheina,e,b
a Centre
Cavaillès, République des Savoirs, CNRS USR3608, Collège de France et École Normale Supérieure, Paris, France
of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA USA
c Laboratoire "Matière et Systèmes Complexes" (MSC), UMR 7057 CNRS, Université Paris 7 Diderot, 75205 Paris Cedex 13, France
d Institut d’Histoire et de Philosophie des Sciences et des Techniques (IHPST) - UMR 8590, 13, rue du Four, 75006 Paris, France
e Institut d’Études Avancées de Nantes, France.
b Department
Abstract
The principle of inertia is central to the modern scientific revolution. By postulating this principle Galileo at once
identified a pertinent physical observable (momentum) and a conservation law (momentum conservation). He then could
scientifically analyze what modifies inertial movement: gravitation and friction. Inertia, the default state in mechanics,
represented a major theoretical commitment: there is no need to explain uniform rectilinear motion, rather, there is a
need to explain departures from it. By analogy, we propose a biological default state of proliferation with variation and
motility. From this theoretical commitment, what requires explanation is proliferative quiescence, lack of variation, lack
of movement. That proliferation is the default state is axiomatic for biologists studying unicellular organisms. Moreover,
it is implied in Darwin’s “descent with modification”. Although a “default state” is a theoretical construct and a limit
case that does not need to be instantiated, conditions that closely resemble unrestrained cell proliferation are readily
obtained experimentally. We will illustrate theoretical and experimental consequences of applying and of ignoring this
principle.
Keywords: default state, theory, organicism, emergence, mathematical symmetries, biological organization
...we should supplement Virchow’s well-known
tenet of the cell theory: "Omnis cellula e cellula,"
by its counterpart: "Omnis organisatio ex
organisatione." If the former denies spontaneous
generation of living matter, the latter denies
spontaneous generation of organization. In
admitting this, we merely paraphrase what
Whitman has called the "continuity of
organization." But within these specified limits the
cell, even in development, is still, as Schwann has
as said, an individual.
Weiss, P. (1940). The problem of cell individuality
in development. The American Naturalist, 74:34-46
∗ Corresponding
author
Email addresses: [email protected] (Ana M. Soto),
[email protected] (Giuseppe Longo), [email protected] (Maël
Montévil), [email protected] (Carlos Sonnenschein)
URL: http://www.di.ens.fr/users/longo/ (Giuseppe Longo),
http://montevil.theobio.org (Maël Montévil)
• Published as: Ana M. Soto, Giuseppe Longo, Maël Montévil,
Carlos Sonnenschein, The biological default state of cell proliferation
with variation and motility, a fundamental principle for a theory of
organisms, Progress in Biophysics and Molecular Biology, Available
online 2 July 2016, ISSN 0079-6107, http://dx.doi.org/10.1016/
j.pbiomolbio.2016.06.006
Preprint submitted to Progress in biophysics and molecular biology
1. Introduction
Biologists and philosophers have long pondered the differences between inert matter and living entities. Rather
than concentrating on this type of comparison, we will
mention some compelling characteristics of the living that
should be taken into consideration when addressing biological phenomena. They are: agency (the capacity to initiate
action1 ), normativity (the capacity of generating their own
rules), individuation (the ability to change one’s own organization), the propensity to become sick, and the return to
health. In this regard, Bichat referring to physical deformities stated: “Whereas monsters are still living beings,
there is no distinction between normal and pathological
in physics and mechanics2 ”. The distinction between the
normal and the pathological holds for living beings alone”.
Inspired by Canguilhem, we will add that the opposite
of pathological is not “normal” but “healthy” (Canguilhem
1991). This is illustrated by the fact that individuals experiencing situs inversus totalis (heart in the right side, liver
in the left side) may be perfectly healthy without being
normal.
These definitions of agency, normativity and individuality are
chosen because they are brief and broadly useful. They have been
discussed more extensively (Burge 2009; Moreno and Mossio 2015)
and PA Miquel this issue)
2 Quoted by (Canguilhem 2008) page 90
1
September 5, 2016
There are differences between the inert and the alive,
and thus between the sciences that study them (Longo and
Soto, this issue). In this regard, it is pointless to try to
fit biology into physics, as one would when thinking that
because a prebiotic world preceded the advent of life, life
would represent a particular case of the physical “world”.
In fact, scientists do not directly deal with the “real world”
but with scientific disciplines constructed by the human
mind to understand such a world. Hence, when we refer
to the physical or biological, we are referring to the disciplines that address inert and living matter, respectively.
Thus, we can only talk about the coherence between the
two disciplines. That is, living matter “obeys” the laws
of physics, but additional principles and observables may
be necessary to understand organisms. When biology is
interpreted as “extended physics” the inert state of matter can be considered as a special case or a singularity of
the living state of matter. In this case, physics is biology
when all organisms are ignored or dead. In science, similar
conceptual transitions already exist: after Riemann, Euclidian Geometry instead of being considered the ultimate
foundation of mathematics has been viewed as a special
case, a singularity: Riemann’s geometry on space of no
curvature (that is, curvature 0).
Before the 20th century, biologists often explicitly stated
the philosophical bases for their observations, experiments
and theories. Two examples of this practice are Blumenbach’s correspondence with Kant about a “formative force”
(Lenoir 1982) and Darwin’s explicit mention of being influenced by Whewell (Ruse 1975). In the preceding articles
of this issue we have addressed the role of theory on the
choice of the observables and the construction of objectivity, particularly the founding role of Galileo’s inertia in
classical mechanics. This principle represents a limit case:
if no cause (a force) modifies the properties of an object,
the object conserves its properties. In the rigorous mathematical sense, this is a limit or asymptotic case since there
are always frictions and gravitational forces and no physical body can be exactly identified to a point-mass moving
on a Euclidean straight line. For didactic purposes we
use the term “default state” (borrowed from computer science) to denote a state that applies when “no action is
taken”. In short, the default state is what happens when
nothing is done to the intended object or system in question. Galileo’s choice of inertia as a fundamental theoretical postulate was counter-intuitive because objects present
in our immediate surroundings are subject to forces that
hinder the manifestation of such a state. The counterintuitiveness of Galilean inertia is illustrated by the fact
that Kepler and Leibnitz thought that the opposite was
true, namely, that “The globe [meaning a planet] has a
natural inertia or stillness, for which it remains at rest in
every place, where it is posed alone [quoted in: (Bussotti
2015)].
The crucial point is that accepting inertia as a postulate implies that we do not need to explain uniform rectilinear motion, rather, we need to explain departures from
it. The usefulness of this postulate remains uncontested in
classical mechanics. In fact, 300 years after Galileo, this
counter-intuitive postulate was buttressed by E Noether’s
theorems; they provided a deeper understanding of inertia
by justifying conservation properties of energy and momentum on the basis of time and space symmetries, respectively (van Fraassen 1989). Ever since, symmetries
(and their breaking) acquired an even more fundamental
role in physics.
In short, the conservation of these symmetries is based
on the idea that the ‘laws’ of physics are the same at different positions and times. In spite of the advance due
to Noether’s theorem, the notion of symmetries is already
used in Archimedes’ law of the lever: equal weights at
equal distances are in equilibrium. This article proposes
a biological default state which would play a comparable
useful role in organismal biology.
2. Existing biological theories
Biology has one comprehensive theory, the theory of
evolution which encompasses the time-scale of phylogenesis and is based on two principles, i) reproduction with
modification, and ii) natural selection. In contrast, a theory of organisms encompassing the time-scale of a life cycle
has yet to be formulated. The theoretical wealth of biology
is manifested by the various theories that address important but more restricted areas of biology, such as the cell
theory, the chromosome theory, the germ theory of disease,
etc. Among those, the one relevant to this chapter is cell
theory, which postulates that cells i) are the basic unit of
life, ii) are made from pre-existing cells, and iii) that organisms are made up of one or more cells and extracellular
matrices, which are made by cells.
The cell theory is central to both ontogenesis and phylogenesis. Regarding the former, multicellular organisms
develop from a zygote, that is at the same time a cell and
an organism (Soto et al. 2008). Regarding phylogenesis,
all existing living organisms are believed to have a common
unicellular ancestor. Using cell theory as a starting point
we postulate a biological default state as a step towards
building a theory of organisms and their ontogenesis.
3. The biological default state
Let’s assume for the sake of argument that we could
observe the moment that life emerged from the pre-biotic
soup. . . . What would have been the properties of this
first cell? Is it reasonable to infer that it would do pretty
much the same as unicellular organisms do today? Indeed,
microbiologists agree that unicellular organisms spontaneously proliferate as long as their milieu provides sufficient nutrients and appropriate ranges of pH, temperature
and pressure. They would also agree that motility is commonplace in unicellular prokaryotes and eukaryotes; by
motility we mean the ability to initiate movement. Motility is perhaps the most obvious instantiation of agency,
2
i.e., the characteristic that makes the intuitive distinction
between alive and inert3 .
In biology, we propose a default state of proliferation with variation and motility , which is common
to all prokaryotic and eukaryotic cells, meaning all those
that are unicellular organisms and those that form part
of multicellular ones. In other words, paralleling the concept of inertia in classical mechanics, proliferation, variation and motility, require no explanation in biology. On
the contrary, hindrances to the expression of default state,
namely, proliferative quiescence, lack of variation, and lack
of movement require an explanation. There is, however, a
fundamental difference between the default state in mechanics and in biology. While the former is about invariance (of momentum in particular) and conservation of
symmetries (of space-time), the latter is about symmetry
changes.4 These differences between theories of the inert
and of the living are discussed in greater detail in Longo
and Soto, this issue, and (Longo et al. 2015).
Soto 1999) and by experimental evidence (Sonnenschein
and Soto 1999; Soto and Sonnenschein 1985; Sonnenschein
et al. 1996; Leitch et al. 2010; Ying et al. 2008).
The default state is exemplified by the behavior of
estrogen-responsive cells like those in the mammary gland.
When given to a sexually immature animal, estrogen will
induce the growth of the ductal tree of the mammary
gland. This effect was interpreted as evidence that estrogen induces the proliferation of the epithelial cells that
form the ductal tree. However, when removed from the organism, these cells proliferate maximally in the absence of
estrogen. Also, when estrogen-free blood serum is added
to the culture medium, it induces a dose-dependent inhibition of cell proliferation, which is manifested as a cell
cycle arrest in the Go-G1 phase of the cell cycle. Only
after this inhibition takes place, is estrogen necessary to
overcome such inhibition (Figure 3.1) (Sonnenschein et al.
1996); indeed, estrogen neutralizes the action of the serumborne inhibitor. The default state of proliferation has been
adopted advantageously as a fundamental principle in theories of carcinogenesis and of development (Sonnenschein
and Soto 1999; Soto and Sonnenschein 2010; Minelli 2011).
3.1. Proliferation
As mentioned above, a “default state” is a theoretical
construct, a limit case, and thus does not require experimental confirmation. However, this fact does not mean
that it lacks an experimental correlate. Galileo conceptualized the principle of inertia through experimentation
using ramps. He gave sufficient evidence to justify the hypothesis that the Aristotelian ideas where every motion
requires a moving force and where the tendency of objects
is to remain at rest were wrong. Based on the experimental observations whereby Galileo was changing the influence of gravity and friction on the motion of an object,
he dared to imagine a “limit” case where no forces were
acting upon the object. Inertia is not a figment of the
imagination; we can experience it when riding a vehicle
that suddenly and forcefully stops. Similarly, in biology
there are natural and experimental conditions that closely
resemble unrestrained cell proliferation; these are instantiated in prokaryotes and unicellular eukaryotes, like
yeast, when growing in a nutrient-rich environment, and by
cells from multicellular eukaryotes when placed in culture
conditions in a nutrient-rich medium. We posit that from
LUCA (the Last Universal Common Ancestor) on, proliferation has been retained as the default state with the advent of multicellular organisms (metaphyta and metazoa).
This conclusion is supported by the conservation of cell cycle components throughout eukaryotes (Sonnenschein and
3 Inert definition: having no inherent power of action, motion, or
resistance (http://dictionary.reference.com/browse/inert).
3.2. Variation
Variation, an integral part of the biological default
state, is readily generated with each cell division. It manifests itself as the unequal distribution of macromolecules
and organelles following cell division, and it is related to
the low number of these intracellular components (Huh
and Paulsson 2011). Additional variation is generated by
the inherent stochasticity of gene expression which leads to
intrinsic cell-to-cell variation of mRNA and protein levels
(Kupiec 1983; Taniguchi et al. 2010; Tyagi 2010; Marinov
et al. 2014; Raj and Oudenaarden 2008). Another source
of variation is generated by somatic mutations and aneuploidy, that, contrary to conventional wisdom suggesting
that these events only occur in cells in a neoplastic state,
were described in cells of normal mammalian organs, like
kidney, liver and brain (Martin et al. 1996; Rehen et al.
2001). In this new context, aneuploidy is seen as a common and advantageous outcome; near 50% of liver cells
are aneuploid and probably because of it livers are better adapted to toxic injury (Duncan et al. 2012; Rehen
et al. 2005). Variation is also generated at supracellular levels of organization (Montévil et al, this issue), like
during branching morphogenesis. We have referred to this
supracellular source of variation when positing the framing principle of non-identical iteration of morphogenetic
processes (Longo et al. 2015); Montévil et al, this issue;
Montévil, Speroni and Soto, this issue).
4 Theoretical symmetries are transformations that do not change
the intended aspect of an object (or mathematically of an equation).
For example, the equation of classical gravitation does not depend
on the time or location of the objects considered, only their mass and
relative distance matter. Theoretical symmetries have a fundamental
role in physics making possible its formalization by using mathematical tools and concepts (van Fraassen 1989; Bailly and Longo 2011;
Montevil et al. this issue).
3.3. Motility
Motility, the third component of the biological default
state, encompasses intracellular, cellular, tissue and organismic non-random movements (Stebbings 2001). From
gliding to swarming or swimming, the motility of microorganisms immediately suggests the idea of agency, and in
3
Figure 1: Experimental examples of the default state.
Panel A: Schematic view. Left, the blue estrogen-target cells proliferate in serumless medium regardless of the presence of estrogen. Middle,
cells are constrained from proliferating by serum. Right, estrogen cancels the serum inhibition and cells proliferate.
Panel B: Schematic representation of serum inhibition. Cells proliferate maximally in the absence of serum supplement when similar numbers
of estrogen-target cells are cultured in a defined medium containing nutrients. The addition of estrogen-free human serum resulted in a
dose-dependent inhibition of cell proliferation. Addition of estrogen does increase cell numbers in serumless conditions; instead it neutralizes
the inhibitory effect of serum ( ____ with estrogen, ———- without estrogen).
Panel C: Effect of serum inhibitor (recombinant serum albumin) on the cell cycle profile of estrogen target MCF7 cells at 24h. Cells in
medium containing HAS are predominately arrested in G1. Almost half of the cells in media containing HSA and estrogen are undergoing
DNA synthesis (S phase of the cycle).
4. 4 The usefulness of the concept of inertia and
default state in biology
fact, the organism uses these movements to migrate to
more suitable environments (Jarrell and McBride 2008).
To do so, they use sensors for attractants and repellents.
Motility is not synonymous with locomotion. For example,
plants that are attached to the ground by their roots cannot move from one location to another one, but they can
make their parts move, as when growing towards a source
of light. Flowers and leaves open and close in response to
light (van Doorn and van Meeteren 2003), and like animal
cells, can move organelles using actin and myosin (Ueda et
al. 2010). In summary, like the mechanical default state,
the biological one is a limit case which is theoretically derived from actual experimental observations.
4.1. The Hardy-Weinberg equilibrium
The introduction of inertia by Galileo, a simple and
universal principle which applies to both celestial bodies
like planets and stars and to terrestrial ones, like apples
and cannon balls, was reformulated by Newton as the first
law of motion. In addition to the indisputable founding
theoretical value of such a principle in its realm of classical
mechanics, it inspired evolutionary biologists to develop
their own founding principle. Indeed, early in the 20th
century population geneticists formulated a principle that
allowed them to study the effect of several “forces”, namely
mutation, selection, mate choice, on the allelic frequencies
of target populations. This is the Hardy-Weinberg equilibrium principle which states “that allele and genotype
frequencies in a population will remain constant from gen4
eration to generation in the absence of other evolutionary
influences”. In other words, Hardy–Weinberg equilibrium
describes an ideal condition against which the effects of
these forces can be analyzed (Edwards 1977).
Unlike Newton’s law, the Hardy-Weinberg equilibrium
does not constitute a founding principle of biology, but an
epistemic tool to study the factors that will negate such
equilibrium, like selection. Loosely related to this use,
epidemiologists who as population geneticists deal with
large populations and statistics, took from the latter the
idea of a null hypothesis representing the possible outcome
that chance is only responsible for the observed results.
Again, the epistemic value of these tools is that it fixes a
“no-change” hypothetical condition against which to study
change.
Figure 2: S.J. Gould proposed a wall of minimal complexity to the
left of which life is not possible. Proliferation increases the biomass
while creating diversity. The asymmetry resulting from the left wall
results in increased average complexity.
4.2. The Zero Force Evolutionary Law
Quite recently, some evolutionary biologists criticized
the Hardy-Weinberg equilibrium when taken as a founding principle. More precisely, Brandon and McShea stated
that quite to the contrary of the stasis represented by
Hardy-Weinberg, their view of “the zero-force evolutionary
law” is the constitutive tendency for diversity and complexity to increase (Brandon and McShea 2012). In contraposition to the Hardy-Weinberg equilibrium, by adopting the
zero-force evolutionary law what requires explanation is
stasis. By claiming that the “. . . default condition of evolutionary systems is change, and change of a particular
sort—increase of diversity and complexity”, these authors
elevate their “zero-force evolutionary law” to a natural condition, that is, a situation for which there is empirical evidence (Brandon and McShea 2012; Gouvêa 2015). We are
now full circle back to the point where we described inertia
as a limit case derived from empirical evidence. Additionally, this zero-force evolutionary law, like the biological
default state, is about change.
of a more general phenomenon, which was proposed by
S.-J. Gould (Gould 1996) and closely analyzed in (Bailly
and Longo 2009) and (Longo and Montévil 2014). Gould
proposed a “left wall” of minimal organismal complexity,
such as that of bacteria, beyond which life is not possible
(Figure 4.3).
From this initial stage (proliferation with variation),
the expression of the default state results in the increase
of the biomass while creating diversity. Like a gas exploding against a wall, the diffusion of the biomass generated
by the default state is asymmetric, resulting in increased
average complexity. This means that there is no need for
any sort of evolutionary pressure towards higher complexity. Indeed, the curve proposed by Gould as a preliminary
mathematical description of this spreading of life may be
fully reconstructed with a diffusion equation that includes
the dynamics of asymmetric boundary conditions (the left
wall)(Bailly and Longo 2009; Longo and Montévil 2014).
This is done by assuming that evolution follows a variability law, which is a consequence of the default state..
As a consequence of the original asymmetry and the default state, complexity can only increase on average, with
no need to assume this increase as a principle. In this
way, two very simple assumptions produce a strong consequence. 6 . Indeed, this structure of reasoning also applies
to the evolution of other organismal quantities, such as
body mass, as long as the ancestor organism has a low
value for this quantity when compared to their descendants. Thus, the “diffusion” following from the instantiation of the default state will result in an average increase of
the considered quantity over evolution. In particular, the
default state justifies the diffusion equation used to model
4.3. The Zero Force Evolutionary Law: a consequence of
the default state
We consider that the “zero-force evolutionary law” is
not the biological first law. Instead, the “zero-force evolutionary law” is the consequence of the biological default
state, which is the generator of intrinsic variation5 . The
general tendency of biological evolution towards an increase of the average complexity is compatible with the
fact that some species have lost appendages, structures or
organs and become less complex under various complexity measurements. We consider this fact as a consequence
5 It is worth noting that the authors of this Chapter independently arrived at the conclusion that the “zero force evolutionary
law” is not a principle. While Soto and Sonnenschein proposed that
the generation of variation by the default state is the condition of
possibility for the zero-force evolutionary law, Longo and Montévil
derived the increasing diversity and "complexity" in evolution from
the asymmetric random diffusion principle they postulated (Longo
and Montévil 2014), p229).”
6 In (Bailly and Longo 2009) a detailed, yet preliminary, measure
of organismal complexity is formalized, which refines Gould’s informal scheme, and set the basis for the proposal of a “hallmark” of
cancer in (Longo et al. 2015). As a matter of fact, cancer seems to
be the only pathology where decreasing functionality (of organs) is
correlated to increasing complexity (of tissues: folding, fractal structures, increasing number of lumena).
5
the evolution (and overall increase) of the mass of mammals in combination with a selective pressure against this
increase (Clauset and Redner 2009). It follows that the
same reasoning would apply mutatis mutandis to different
measures of complexity, provided they follow the above
assumptions. Again, the default state principle has more
generality than the “zero-force evolutionary law”; meaning
that the latter may be understood as a consequence of the
former.
the study of bacterial nutrition. Any substance that improved bacterial propagation was called a “growth factor”.
In modern microbiology textbooks, growth factors are defined as substances required in small amounts by unicellular organisms because they fulfill specific roles in the
biosynthesis of the organism’s own components. A growth
factor is necessary when a metabolic pathway is missing
or is blocked. In this context growth factors are purines
and pyrimidines, amino acids and vitamins.
At the time when several groups attempted to develop
methods to culture cells isolated from metazoan organisms, research on bacterial metabolism and nutrition was
flourishing. Among those groups, Margaret and Warren H.
Lewis at Johns Hopkins University empirically created artificial conditions of life while wishing to have control over
these cells. For the Lewises, cells were not agents. Instead, they thought that in order to grow the cells needed
to be “stimulated” to proliferate as if they were as passive
as inert objects. In hindsight, we now know that when
freshly isolated cells fail to thrive it is not due to them being quiescent but because they die. Slowly but inexorably,
the operational concept of “growth factor” became established within the field of tissue culture as a specific “signal”
to induce a passive cell to proliferate (Sonnenschein et al.
2013).
The idea of a “program” in biology reinforced the view
that cells need to receive “information” or “signals” in order
to proliferate and to move. When applying this thinking to
the initial cell at the beginning of life what or who would be
the purveyor of such stimuli? From our perspective, cell
culture represents a state of de-emergence, whereby the
cells that form part of an organism are “liberated” from
the constraints imposed by that organism. Under extraorganismic (in culture) conditions, these cells regain properties that mimic those of the unicellular organisms from
which the multi-celled organism eventually evolved. This
brings up the relevance of placing cell and tissue culture
under an evolutionary perspective. The pioneers of tissue
culture failed to apply evolutionary theory when venturing
into quasi-artificial life (Maienschein 1983). In hindsight,
this was a squandered opportunity to recognize that in
the quasi-artificial life of the culture flask, metazoan cells
behave as unicellular organisms, and thus exert their constitutive ability to proliferate and move, properties that
enabled the LUCA to generate all the diversity of life on
earth that we recognize today.
5. From inertia to operational definitions
Given that evolutionary biologists used the principle
of inertia in the first decade of the 20th century, why is it
that organismal biologists have yet to develop comparable
theoretical constructs? We attribute this lack of theoretical thinking in organismal biology to the belief expressed
by many biologists in the first half of the 20th century that
facts “speak for themselves” (see Perret et al in this issue),
and later, to the adoption of the mathematical theory of information without critical examination. This brought the
metaphorical use of the concepts of information, program
and signal to biology hindering its progress (Longo et al.
2012). Regarding the former, organismal biologists tend
to believe that they observe the “real world” and thus that
data are objective. Contrary to this belief, data are theory laden, and thus one should examine the hidden philosophical content of “data”. Another important factor in
this discussion is that, lacking global theories, operational
thinking plus dubious common-sense beliefs become the
substitute for theories. In operationalism, scientific terms
are defined by the experimental operations which determine their applicability (Hull 1968).
5.1. The operational origins of hormones and growth factors
Surgical removal of the gonads results in atrophy of
the accessory sex organs (uterus, prostate). This noncontroversial fact prompted the search for “factors” secreted by gonads that made the accessory organs grow
in size, due to an increase of their cell number and in the
deposition of extracellular matrix. Administration of gonadal extracts resulted in the reversal of this atrophy and
in due turn, the substances that produced these trophic
effects were identified. They were named “hormones”, and
were defined operationally as the substances that, in their
bioassays, induced the growth of the target organs. The
operational nature of this definition was soon forgotten
and it became a “fact” that hormones directly stimulate
proliferation., Despite evidence to the contrary, this notion remains engrained among specialists (Sonnenschein
and Soto 1999).
The concept of “growth factor” appeared in the early
20th century when biologists, having succeeded in propagating bacteria in medical laboratories using meat broth
and other complex extracts and body fluids, turned to
5.2. From operational definitions to “the law of the land”
As mentioned above, microbiologists accept as fact that
unicellular organisms constitutively proliferate in the presence of nutrients (proliferation is their default state). Obviously, cells in multicellular organisms do not exhibit unconstrained cell proliferation. Below we transcribe the
standard explanation for this difference from a widely used
textbook. “Unicellular organisms tend to grow and divide as fast as they can, and their rate of proliferation
6
depends largely on the availability of nutrients in the environment. The cells of a multicellular organism, however,
divide only when the organism needs more cells. Thus, for
an animal cell to proliferate, it must receive stimulatory
extracellular signals, in the form of mitogens, from other
cells, usually its neighbors. Mitogens overcome intracellular braking mechanisms that block progress through the
cell cycle.”(Alberts et al. 2014)
From the above analysis about inertia and a biological default state, what exactly is objectionable in the just
quoted textbook account of this difference? The quotation
acknowledges that unicellular organisms have proliferation
as their default state. Next, it moves to multicellular organisms and, it states the obvious: that cells in multicellular organisms do not proliferate despite plenty of nutrients being available. From there, while using common
sense, the sense that Galileo systematically disregarded,
the quotation claims as a fact that animal cells are quiescent and need stimuli, i.e. signals to proliferate. This
option implies a reversal of the default state taking place
with the advent of multicellularity. However, no explanation is given about the acknowledged fact that metaphyta
conserved proliferation as the default state, or that the cell
cycle components are conserved through evolution; altogether, these pieces of evidence strongly suggest that there
was no change of default state in the cells of multicellular
organisms. The concept that the default state could be
constrained in animals, namely, that an additional layer
of regulation emerged during the advent of multicellularity, was not contemplated by the authors of the textbook
referred to above.
Since the introduction of the concept of a biological
default state operating in all cells (Soto and Sonnenschein
1991), researchers dealing with the phenomenon of lymphocyte quiescence found that quiescence is an induced
state, namely that proliferation is actively constrained.
Separately, other researchers concluded that embryonic
stem cells proliferate constitutively, a phenomenon they
called “ground state” (Ying et al. 2008; Leitch et al. 2010).
In both cases, proliferation as a default state was interpreted as a peculiarity of the particular experimental model
being investigated. The absence of a bold attempt to generalize these findings to all cells is probably due to a dominant perception among biologists that there are neither
laws nor rules in biology. Finally, and most fundamentally, in the absence of a global theoretical framework that
constructs objectivity and determines the proper observables, organismal biology appears as less intelligible given
that new results create more contradictions that happily
coexist and are never discarded.
organisms manifested as the constitutive ability to reproduce and generate movement. Equally important, the biological default state ties the source of variation together
with its transmission at each proliferative event. Each cell
division thus represents a symmetry change that generates
two non-identical daughter cells.
A founding principle for a theory of organisms that addresses ontogenesis needs to be compatible with the theory of evolution, which addresses phylogenesis. Below we
address three points in common between these theories,
namely, constitutive reproduction/ proliferation, variation
and historicity.
6.1. Darwin’s limit case and the default state
In the Origin of Species, Darwin stated: “. . . There is
no exception to the rule that every organic being naturally increases at so high a rate, that, if not destroyed,
the earth would soon be covered by the progeny of a single pair” (Darwin 1859). According to Darwin’s theory,
reproduction is linked to modification: in his own words,
“descent with modification”. Reproduction with variation
is intrinsic to organisms regardless of whether they are
unicellular or multicellular (Sonnenschein and Soto 1999;
Soto and Sonnenschein 2011). Darwin’s narrative implies
that reproduction with variation is a default state and he
describes it as a limit case. In fact, because reproduction
and proliferation are the same event in asexual reproduction of unicellular organisms, this default state represents
a common postulate for the theories of evolution and organisms.
6.2. Change, symmetry breaks, and historicity
The theory of evolution addresses the generation of
incessant change (variation in our words, modification in
Darwin’s) upon which natural selection operates; the result is phenotypic diversity. The incessant changes of life
processes may be analyzed as extended critical transitions
(Bailly and Longo 2011; Longo and Montévil 2014). Under our theoretical approach, throughout its ontogeny, an
organism may be understood as being in a permanent transition with all the main signatures of criticality, such as
changes of symmetries and the formation of a new global
structure (Longo et al. 2015). In an organism, each cell
division changes local symmetries because each of those
divisions forces new local and global correlations. These
changes yield variability and adaptability to organisms. In
the context of evolution, the advent of new functions and
organs are additional examples of symmetry changes.
Far-from-equilibrium, self-organizing physical systems
have been used as a starting point to understand complex biological organization. These physical systems are
understood by the analysis of their instantaneous flows.
Indeed, the shape of a flame can be calculated from the
flows of matter that go through it, whereas the shape of
an organism cannot. Far from equilibrium systems appear
spontaneously and can be analyzed independently. In contrast, organisms are not spontaneous but historical; that
6. The biological default state links ontogenesis to
phylogenesis
The biological default state is a founding principle upon
which a theory of organisms and of their ontogenesis can
be constructed. It takes into consideration the agency of
7
Acknowledgements:
is, they are a consequence of the reproductive activity of
a pre-existing organism. Organization cannot be deduced
from flows operating within and upon organisms; instead,
understanding biological organization requires a historical
analysis, and this applies to the time-scale of ontogenesis
as well as the one of phylogenesis (Longo et al. 2015).
Finally, the recently proposed “zero-force evolutionary
law” (Brandon and McShea 2012; Gouvêa 2015), namely
the constitutive tendency for diversity and complexity to
increase throughout evolution is not a default state or principle, but a derived property of the biological default state.
The zero-force evolutionary law stresses increasing complexity and diversity. As we mentioned above in reference
to Gould’s work, this tendency may be seen as a consequence of i) the agency of living matter instantiated by
the biological default state of proliferation with variation
and motility, and of ii) natural selection, once this increase
of diversity and complexity is analyzed in the global terms
of an asymmetric diffusion from the least (bacterial) complexity.
This work was conducted as part of the research project
“addressing biological organization in the post-genomic era”
which is supported by the International Blaise pascal Chairs,
Région Île-de-France. Additional support to AMS was provided by Grant R01ES08314 (P.I. AMS) from the U. S.
National Institute of Environmental Health Sciences. Maël
Montévil is supported by Labex "Who am I?", laboratory
of Excellence No. ANR-11-LABX-0071. The funders had
no role in the study design, data collection and analysis,
decision to publish, or preparation of the manuscript. The
authors are grateful to Cheryl Schaeberle for her critical
input. The authors have no competing financial interrests
to declare.
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